This proposal has three main objectives. The first is to establish the relevant cytotoxins on ox-LDL toward cell types found at atherosclerotic lesions. This is accomplished by relating quantitation data of the relative amounts of potent toxins formed, the degree of oxidative modification of LDL and the relative toxicities of these toxins toward smooth muscle cells, endothelial cells and monocytes. This objective will provide information to determine which of these toxins are relevant in vivo. The second objective is to characterize the mechanisms by which select toxins of ox-LDL induce cell injury and death. Mechanisms to be examined include lipid peroxidation, damage to cellular membranes, altered cholesterol synthesis and the role of new protein synthesis. A better understanding of these mechanisms may aid in developing potential treatments of atherosclerosis. The third objective of the proposal is to examine the role of cellular antioxidant defenses. The aim is to determine what role, if any, catalase, superoxide dismutase and glutathione peroxidase have in protecting cells from potent lipoprotein oxidation products such as 7-hydroperoxycholesterols, 7- hydroxycholesterols, 7-ketacholesterol, cholesterol epoxides, lysophosphatidylcholine and 4-hydroxynonenal. This information may provide the basis for understanding differences in susceptibility to atherosclerosis.